PARK9-linked parkinsonism in eastern Asia: Mutation detection in ATP13A2 and clinical phenotype

Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Neurology (Impact Factor: 8.3). 02/2008; 70(16):1491-1493. DOI: 10.1212/01.wnl.0000310427.72236.68
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    ABSTRACT: Background It has been reported that the ATP13A2 gene is one of the most susceptible pathogenic genes of Parkinson’s disease (PD). PARK9 mutations are found in early-onset PD and familial PD patients. Uygur and Han PD patients in the Xinjiang area were recruited as research subjects to study the differences in the Thr12Met and Ala1144Thr loci mutations of the ATP13A2 gene in these PD populations. This study explored the mutations at the Thr12Met and Ala1144Thr gene loci of the ATP13A2 gene in Parkinson’s disease patients in the Uygur and Han populations in the Xinjiang province. Material/Methods The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to analyze the Thr12Met and Ala1144Thr mutations of the ATP13A2 gene in a case-control study of 200 age- and sex- matched Uygur and Han PD patients. Results Of the 200 PD patients were studied, 2 from the Han group had a Thr12Met mutation, but Ala1144Thr mutations were not found. Among the Uygur PD patients, no Thr12Met or Ala1144Thr mutations were found. Conclusions Thr12Met and Ala1144Thr mutations of the ATP13A2 gene are rare in the Uygur PD patients in Xinjiang. Overall, the mutation rates of Thr12Met and Ala1144Thr in the Uygur and Han PD patients in the Xinjiang region are low.
    Medical science monitor: international medical journal of experimental and clinical research 11/2014; 20:2177-82. DOI:10.12659/MSM.892821 · 1.22 Impact Factor
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    ABSTRACT: Parkinson's disease is a multifactorial disorder with several genes linked to the familial types of the disease. ATP13A2 is one of those genes and encode for a transmembrane protein localized in lysosomes and late endosomes. Previous studies suggested the roles of this protein in lysosomal functions and cellular ion homeostasis. Here, we set out to investigate the role of ATP13A2 in lysosomal function and in metabolism of α-synuclein, another PD-linked protein whose accumulation is implicated in the pathogenesis. We generated non-sense mutations in both copies of ATP13A2 gene in SH-SY5Y human neuroblastoma cells. We examined lysosomal function of ATP13A2-/- cells by measuring the accumulation of lysosomal substrate proteins, such as p62 and polyubiquitinated proteins, induction of acidic compartments, and degradation of ectopically introduced dextran. None of these measures were altered by ATP13A2 deficiency. The steady-state levels of α-synuclein in cells or secretion of this protein were unaltered either in ATP13A2-/- compared to the normal cells. Therefore, the proposed roles of ATP13A2 in lysosomal functions may not be generalized and may depend on the cellular context. The ATP13A2-/- cells generated in the current study may provide a useful control for studies on the roles of PD genes in lysosomal functions.
    12/2014; 23(4):365-71. DOI:10.5607/en.2014.23.4.365
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    ABSTRACT: Parkinson's Disease (PD) is a complex and multifactorial disorder of both idiopathic and genetic origin. Thus far, more than 20 genes have been linked to familial forms of PD. Two of these genes encode for ATP13A2 and alpha-synuclein (asyn), proteins that seem to be members of a common network in both physiological and disease conditions. Thus, two different hypotheses have emerged supporting a role of ATP13A2 and asyn in metal homeostasis or in autophagy. Interestingly, an appealing theory might combine these two cellular pathways. Here we review the novel findings in the interaction between these two proteins and debate the exciting roads still ahead.
    12/2014; 23(4):314-23. DOI:10.5607/en.2014.23.4.314